This Project 1 proposal is part of a revised renewal application for the CORT Program entitled Translating molecular signal pathways to orthopaedic trauma care. During the previous funding period, we published results contributing to the general hypothesis that inappropriate articular chondrocyte (AC) hypertrophy is a mechanism of OA pathogenesis. Given that PTH 1-34 (teriparatide) is an inhibitor of hypertrophy and inducer of matrix synthesis in chondrocytes, several of our recent breakthrough discoveries have solidified rationale for its use as a novel therapy for OA. Most important is our remarkable finding that teriparatide has dramatic chondro- regenerative effects in a mouse model of injury-induced knee OA. This is plausible mechanistically based on our published result that teriparatide induces the cyclinDI-dependent degradation of Runx2 in chondrocytes. Since Forteo (teriparatide) is already FDA-approved, and since patients enrolled in the NIH-sponsored OAI that were prescribed Forteo for osteoporosis had improved WOMAC knee function scores compared to matched controls, the rationale for clinical study is compelling. Based on this series of findings, we propose a continuation of this project that involves testing the following central hypotheses: The chondro-protective and -regenerative effect of teriparatide in murine posttraumatic OA involves stimulation of matrix production coupled with the inhibition of inappropriate articular chondrocytes maturation that is mechanistically linked to a reduction/inhibition of RUNX2. To address this hypothesis, we propose the following 3 Specific Aims: 1) To establish that the chondro-regenerative effects of teriparatide in posttraumatic knee OA are mediated by articular chondrocytes, 2) To characterize the molecular basis for the stimulation of matrix production and the inhibition of maturation induced by teriparatide in articular chondrocytes, and 3) To investigate the role of Jag1/Notch signaling in the effects of teriparatide on arthritic cartilage. If successful, completion of these aims will establish teriparatide as a candidate therapy for OA, a disease that currently is only treated palliatively.